Repression of Multiple Myeloma Cell Growth In Vivo by Single-wall Carbon Nanotube (SWCNT)-delivered MALAT1 Antisense Oligos

Abstract

The single-wall carbon nanotube (SWCNT) is a new type of nanoparticle, which has been used to deliver multiple kinds of drugs into cells, such as proteins, oligonucleotides, and synthetic small-molecule drugs. The SWCNT has customizable dimensions, a large superficial area, and can flexibly bind with drugs through different modifications on its surface; therefore, it is an ideal system to transport drugs into cells. Long noncoding RNAs (lncRNAs) are a cluster of noncoding RNA longer than 200 nt, which cannot be translated to protein but play an important role in biological and pathophysiological processes. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a highly conserved lncRNA. It was demonstrated that higher MALAT1 levels are related to the poor prognosis of various cancers, including multiple myeloma (MM). We have revealed that MALAT1 regulates DNA repair and cell death in MM; thus, MALAT1 can be considered as a therapeutic target for MM. However, the efficient delivery of the antisense oligo to inhibit/knockdown MALAT1 in vivo is still a problem. In this study, we modify the SWCNT with PEG-2000 and conjugate an anti-MALAT1 oligo to it, test the delivery of this compound in vitro, inject it intravenously into a disseminated MM mouse model, and observe a significant inhibition of MM progression, which indicates that SWCNT is an ideal delivery shuttle for anti-MALAT1 gapmer DNA.

Alveolar macrophage secretion of vesicular SOCS3 represents a platform for lung cancer therapeutics

“…These include pharmacologic inhibitors of STAT activation (e.g., ruxolitinib) as well as exogenous expression of SOCS3 via viral vectors (7,24,25) and administration of SOCS peptides (8,26). STAT inhibitors, while promising in hematological cancers such as multiple myeloma (27), failed in clinical drug trials of solid tumors owing to toxicity and tumor resistance due to pathway compensation (28). Viral transduction of SOCS3 expression has not yet been tested in humans in vivo; therefore, its effectiveness and safety at this point are unknown.…”

MALAT1 Long Non-Coding RNA: Functional Implications

“…[88,106,107,140,142,[150][151][152]. MALAT1 gapmer oligonucleotides conjugated to single-walled carbon nanotubes delivered systemically into mice resulted in significant inhibition of multiple myeloma growth [153]. Further, small molecules specifically targeting the MALAT1 triple helix structure have been identified and they lay the foundation for new classes of anticancer therapeutics for the treatment and investigation of MALAT1-driven cancers [154].…”

Photoactivatable nanoCRISPR/Cas9 System Based on crRNA Reversibly Immobilized on Carbon Nanoparticles

“…SWCNT and SWCNT-COOH carbon nanoparticles are well-investigated and show good potential as nucleic acids delivery agents [ 27 ]. They have been employed for delivery of siRNA [ 35 , 36 , 37 , 38 ], antisense oligonucleotides [ 39 ], and DNA [ 40 , 41 ]. Earlier we showed that the IC 50 values for the SWCNT-oligonucleotide hybrids are not achieved even at hybrid concentrations of 100 mg/L [ 28 ].…”